Pseudomonas aeruginosa T6SS secretes an oxygen-binding hemerythrin to facilitate competitive growth under microaerobic conditions.

Pseudomonas aeruginosa is a prominent respiratory pathogen in cystic fibrosis (CF) patients, thriving in the hypoxic airway mucus. Previous studies have established the role of the oxygen-binding hemerythrin, Mhr, in enhancing P. aeruginosa's fitness under microaerobic conditions. However, the specific mechanisms by which Mhr operates remain unclear. This study uniquely identifies Mhr as an effector of the H2-Type VI Secretion System (H2-T6SS) and elucidates its role in the transport and interaction mechanisms that confer a growth advantage under microaerobic conditions. Our findings demonstrate that mhr expression is directly regulated by Anr and Dnr. Western blot analysis confirms that Mhr is secreted extracellularly via the H2-T6SS. The oxygen-binding Mhr re-enters P. aeruginosa through the OprG porin. Then, Mhr interacts with cbb3-type cytochrome c oxidase (cbb3-CcO) subunits CcoP1/CcoP2, significantly impacting intracellular NADH/NAD⁺ levels. These insights suggest that the T6SS-mediated secretion and transport of Mhr represent a novel mechanism by which P. aeruginosa acquires and delivers oxygen, potentially enhancing microaerobic respiration, energy production, and growth under microaerobic conditions.